Sterility is one of the most important characteristics of pharmaceutical compositions. Maintenance of sterility of pharmaceutical compositions is a function of both the method of sterilization and the integrity of the packaging or application system. For products that are intended for multiple dosing, antimicrobial agents must be added to the product formulation to protect the product from accidental microbial contamination during its storage or use or both. This is true regardless of the dosage form of the composition.
Stable multi-dose pharmaceutical formulations containing a variety of active ingredients are viewed by the pharmaceutical industry as particularly advantageous and commercially attractive. These formulations are generally, though not always, are packaged in a manner that allows for the extraction of partial amounts of the formulation at various times. This type of system is desirable as it allows multiple doses to be obtained from a single container, and allows for more controlled administration of the pharmaceutical composition as the formulation may be withdrawn and used, applied or administered in any partial amount, and over an extended period of time.
The nature of the use of multi-dose formulations imposes special requirements on the formulation. For example, maintenance of the sterility of a composition is particularly challenging given the many opportunities for introduction of microorganisms and other contaminants into the formulations. Repeated introduction of foreign elements, for example, needles or swabs, into the multi-dose container after formulation also creates a likelihood of introducing microorganisms into the container. Additionally and alternatively, microorganisms may be introduced during filling of the containers or during reconstitution of the formulations after lyophilization and prior to use, application or administration. The extended periods of time over which the container may be stored—especially during multiple introductions of foreign elements, and/or after contaminants may have been introduced, demands that the formulation contain special additives to insure the sterility of the contents.
To insure that these formulations maintain optimally sterile properties, the United States Food and Drug Administration (USFDA) and regulatory agencies in other jurisdictions including in Europe and Japan, require that all multi-dose compositions contain preservatives to prevent the growth of, or to affirmatively kill, any microorganisms that may be introduced into them. The development of preservative-containing multi-dose formulations is challenging, however, because various active ingredients in pharmaceutical compositions tend to interact adversely with preservative compounds.
Possible adverse interactions between preservatives and pharmacologically active ingredients include the degradation of the active ingredients, especially ones stored for extended periods of time; inactivation, neutralization, or alteration of the active ingredients; formation of aggregates comprising the active ingredients and other additives or constituents of the formulations; and other interactions that inactivate, degrade or make the administration of the formulation to humans, by any dosage route, difficult, painful or otherwise undesirable.
Additionally, preservatives themselves are noted for causing acute adverse reactions, such as allergic reactions or even seizures, in humans upon administration. Ideally, a preservative contained in a multi-dose pharmaceutical formulation should be effective in low concentration against a wide variety of microorganisms; soluble in the formulation; non-toxic; compatible and nonreactive with the active ingredient as well as other additives; active with long term stability; and nonreactive with components of the container or closure system.
Sandeep Nema et al. published lists of various excipients that have been included in the formulation of injectable products marketed in the United States. The antimicrobial preservatives listed in this review article are included in Table 1:
TABLE 1ANTIMICROBIAL PRESERVATIVESPreservativeFrequencyRangeBenzalkonium chloride10.02%w/vBenzethonium chloride40.01%Benzyl alcohol740.75–5%Chlorobutanol170.25–0.5%m-cresol30.1–0.3%Myristyl gamma-picolinium20.0195–0.169%chlorideParaben methyl500.05–0.18%Paraben propyl400.01–0.1%Phenol480.2–0.5%2-Phenoxyethanol30.50%Phenyl mercuric nitrate30.001%Thimerosal460.003–0.01%
Despite the range of preserving agents available, finding a reliable, broadly non-reactive preservative or combination of preservatives useful in pharmaceutical compositions remains elusive. Accordingly, there remains a need for a preservative or combination of preservatives that is minimally reactive with active ingredients in pharmaceutical formulations; is minimally reactive with other additives commonly used in multi-dose pharmaceutical formulations; maintains the stability of the active ingredient and the composition over an extended shelf life of the product; meets the United States, European, and Japanese pharmacopia criteria for preservative challenge testing; is safe in the concentrations used; and is administrable—by any parenteral, topical, ocular, inhaled or oral route—in a manner that is effective, and minimizes pain and the chance of adverse reaction, for example, allergic reaction in the patient.